PROJECT SUMMARY The management of gout is suboptimal and complicated by high prevalence of comorbidities, including chronic kidney disease (CKD); 71% of gout patients in U.S. have CKD stage 2 or higher. A key reason for suboptimal gout care is lack of knowledge and acceptance for the utility of lowering serum urate (sUA) levels to < 6 mg/dl (based on the solubility threshold of 6.8 mg/dl), known as treat-to-target (TTT). While a sUA threshold of < 6 mg/dl is valuable for managing gout, it has not been examined for renal function preservation. Recently, the Department of Veterans Affairs (VA) funded a 4-year randomized, double-blinded, non-inferiority ?Stop Gout? (VA CSP594) study with a sUA TTT approach, which will assess the comparative effectiveness of allopurinol vs. febuxostat. Our proposed study, Protecting Renal functiOn with Urate-lowering Drugs (PROUD), a mechanistic ancillary study to this innovative trial, will leverage trial data to assess whether achieving target sUA is valuable for renal function preservation for the first time, with the following two specific aims. Specific Aim 1 is to evaluate the efficacy of sUA lowering and allopurinol and febuxostat dose in preserving renal function in gout patients. We hypothesize that each of the following factors will be positively associated with renal function preservation as assessed by change in eGFR based on serum creatinine at 72-weeks (primary outcome) and serum Cystatin C at 48-weeks (secondary outcome): Achieving a sUA reduction and a target sUA level < 6 mg/dl at 24-weeks (Hypotheses 1a and 1b), baseline CKD Stage 3 (compared to CKD stage 1 or 2; Hypothesis 1c), the final up-titrated allopurinol dose at 21-weeks (Hypothesis 1d), and the final up-titrated febuxostat dose at 18-weeks (Hypothesis 1e). Specific Aim 2 will assess the mechanisms of renal function preservation in gout. We hypothesize that reduction at 24-weeks in each of the following will be associated with renal function preservation at 72-weeks: Renin-angiotensin system activation (plasma renin and aldosterone; Hypothesis 2a), systemic inflammation (IL-1?, IL-6, TNF-?, MCP-1, PDGF, C-reactive protein; Hypothesis 2b), and oxidative stress level (lipid peroxidation by 8-epi-PGF2a; protein oxidation by carbonyl formation, 3-nitrotyrosine formation and reduced thiol status; Hypothesis 2c). PROUD will have high public health impact and will advance the field by addressing unanswered questions related to renal function preservation with XOI in gout and underlying mechanisms. The University of Alabama at Birmingham (UAB) and the University of Nebraska Medical Center (UNMC), two large academic gout and immunology research centers, are ideally positioned to address the clinical and mechanistic questions posed. Our collaborative expertise, complemented by the leveraged resources of the proposed NIAMS supported P50 UAB Center of Research Translation (CORT) will be used to execute this novel translational study.